TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF

ABSTRACT

The present invention is directed to benzyl urea compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence may be useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor Trk-A, Trk-B and/or Trk-C.

FIELD OF THE INVENTION

The invention is directed to a class of substituted ureas, their salts,pharmaceutical compositions comprising them and their use in therapy ofthe human body. In particular, the invention is directed to a class ofsubstituted ureas, which are tropomyosin-related kinase (Trk) familyprotein kinase inhibitors, and hence may be useful in the treatment ofpain, inflammation, cancer, restenosis, atherosclerosis, psoriasis,thrombosis, a disease, disorder, injury, or malfunction relating todysmyelination or demyelination or a disease or disorder associated withabnormal activities of nerve growth factor (NGF) receptor TrkA.

BACKGROUND OF THE INVENTION

Trk's are high affinity binding protein kinase receptors that areactivated by Neurotrophins (NT), a group of soluble growth factors NerveGrowth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF) andNeurotrophin 3-5 (NT 3-5). The Trk's are made up of three family membersTrkA, TrkB and TrkC that bind to and mediate the the signal transductionderived from the Neurotrophins. NGF activates TrkA, BDNF and NT-4/5activate TrkB and NT3 activates TrkC.

Inhibitors of the Trk/neutrophin pathway have been demonstrated to behighly effective in numerous pre-clinical animal models of pain.Antagonistic NGF and TrkA antibodies have been shown to be efficaciousin inflammatory and neuropathic pain animal models and in human clinicaltrials. See Woolf, C. J. et al. (1994) Neuroscience 62, 327-331; Zahn,P. K. et al. (2004) J. Pain 5, 157-163; McMahon, S. B. et al., (1995)Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) Neuroreport 8,807-810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al.(2003) Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol.Motil. 15, 355-361; and Jaggar, S. I. et al. (199) Br. J. Anaesth. 83,442-448. Through gene disruption studies in mice the TrkA-NGFinteraction was found to be required for the survival of certainperipheral neuron populations involved in mediating pain signaling inthe case of pancreatic cancer—an increase in the expression of TrkA wasshown to correlate with an increase level of pain signaling (Zhu et al.,Journal of Clinical oncology, 17:2419-2428 (1999)). Increased expressionof NGF and TrkA was also observed in human osteoarthritis chondrocytes(Iannone et al, Rheumatology 41:1413-1418 (2002)). In particular,anti-TrkA antibodies and anti-NGF antibodies have been demonstrated tobe effective analgesics in in vivo models of inflammatory andneuropathic pain. See WO2006/131952, WO2005/061540, EP1181318 andWO01/78698, WO2004/058184 and WO2005/019266, respectively. See alsoWO2004/096122 and WO2006/137106 which describe the use of an anti-TrkAantibodiy in combination with an opioid analgesic for the treatment orprevention of pain. See also WO2012/158413 and U.S. patent applicationSer. No. 61/650,019.

Trk inhibitors that can induce apotosis of proliferating osteoblast maybe useful in treating diseases related to an imbalance of the regulationof bone remodeling, such as osteoporosis, rheumatoid arthritis and bonemetastases. The expression of TrkA and TrkC receptors in the boneforming area in mouse models of bone facture and localization of NGF inalmost all bone forming cells have been observed (K. Asaumi, et al.,Bone (2000) 26(6) 625-633). See also Exper Opin. Ther. Patents (2009)19(3)), WO2006/115452 and WO2006/087538, WO6123113, WO10033941,WO10077680, WO2005110994, Investigational New Drugs (2004), 22, 449-458and R. Tripathy, et al., Bioorganic & Medicinal Chem Ltrs., 2008, 18,3551-3555. The association between overexpression, activation,amplification and/or mutation of Trks and several cancers as seen withstudies conduct on neuroblastoma (Brodeur, G. M., Nat. Rev. Cancer 2003,3, 203-216), ovarian cancer (Kruettgen et al., Brain Pathology 2006, 16:304-310), prostate cancer (Dionne et al., Clin. Cancer Res. 1998, 4(8):1887-1898), pancreatic cancer (Dang et al., J of Gastroenterology andHepatology 2006, 21(5): 850-858), large cell neuroendocrine tumors(Marchetti et al., Human Mutation 2008, 29(5), 609-616, and colorectalcancer (Bardelli, A., Science 2003, 300, 949) support the reasoning thattherapeutic implications of an effective Trk inhibitor may extend farbeyond pain therapy. See also WO07013673, WO07025540 and WO08052734.

Also promising is the utility of Trk inhibitors in the treatment ofinflammatory lung diseases such as asthma (Freund-Michel, V; et al.,Pharmacology & Therapeutics (2008), 117(1), 52-76), interstitialcyctitis (Hu Vivian Y; et. al., J of Urology (2005, 173(3), 1016-21),inflammatory bowel disease including ulcerative colitis and Chron'sdisease (Di Mola, F. F., et al., Gut (2000), 46(5), 670-678 andinflammatory skin diseases such as atopic dermatitits (Dou, Y. C., et.Al., Archives of Dermatological Research (2006), 298(1), 31-37, eczemaand psoriasis (Raychaudhuri, S. P. et. al., J of InvestigativeDermatology (2004), 122(3), 812-819).

Modulation of the neutrophin/Trk pathway also has been shown to have aneffect in the etiology neurodegenerative diseases including multiplesclerosis, Parkinson's disease and Alzeheimer's disease (Sohrabji, et.al., Neuroendocrinology (2006), 27(4), 404-414).

Thus, the compounds of the invention, which are Trk inhibitors, arebelieved to be useful in the treatment of multiple types of acute andchronic pain including but not limited to inflammatory pain, neuropathicpain, and pain associated with cancer, surgery and bone fracture. Thecompounds may also useful in the treatment of cancer, inflammation,neurodegenerative diseases and certain infectious diseases.

SUMMARY OF THE INVENTION

The present invention is directed to bicyclic compounds of genericformula (I) below or pharmaceutically acceptable salts thereof that maybe useful as a Trk kinase mediator of NGF driven biological responses.

The invention is further directed to methods of treating a patient fordiseases or disorders in which the NGF receptor Trk kinases areinvolved, in particular TrkA. The invention further involves use of thecompounds as NGF receptor TrkA, Trk B and/or Trk C inhibitor and/orantagonist for the preparation of a medicament for the treatment and/orprevention of diseases associated with inhibiting TrkA, Trk B and/or TrkC, which includes pain, cancer, restenosis, atherosclerosis, psoriasis,thrombosis, or a disease, disorder, or injury relating to dysmyelinationor demyelination. The invention is also directed to pharmaceuticalcompositions which include an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, and the use of the compounds andpharmaceutical compositions of the invention in the treatment of suchdiseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to compounds of generalformula I or Ia

and pharmaceutically acceptable salts thereof, wherein:R represents hydrogen, or C₁₋₆ alkyl;R¹ represents a nitrogen containing C₅₋₁₀ heterocycle optionallyinterrupted with 1 to 3 additional heteroatoms selected from S, N, andO, said heterocycle optionally substituted with 1 to 3 groups of R^(a);R² represents —(CR₂)_(n)C₃₋₁₀ cycloalkyl, —(CR₂)_(n)C₆₋₁₀ aryl or anitrogen containing C₅₋₁₀ heterocycle optionally interrupted with 1 to 3additional heteroatoms selected from S, N, and O, said cycloalkyl, aryland heterocycle optionally substituted with 1 to 3 groups of R^(a);R^(a) represents —CN, —O—, —(CH₂)_(n)C₁₋₄haloalkyl, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₁₋₆alkynyl, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀heterocycle, —C₃₋₁₀ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₀ aryl, —O—C₅₋₁₀heterocycle, —C(O)CF₃, —(CH₂)_(n)halo, —OR, —NRR, NHC₆₋₁₀aryl, —SCF₃,SO₂CF₃, OC(F)₂Cl, OC₁₋₄ haloalkyl, C(O)NRR, SO₂R, SO₂NRR, OC(F)₂C(F)₃,S(O)₂CH(F)₂, OC(F)₂CH(F)₂, C(CH₃)₂C≡N, —COC₆₋₁₀ aryl, or —CO₂R, saidcycloalkyl, alkyl, aryl and heterocycle optionally substituted with 1 to3 groups of R^(b);R^(b) represents, —CN, —(CH₂)_(n)C₁₋₄haloalkyl, —OR, —C₁₋₆alkyl,(CH₂)_(n)OR, —(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀ heterocycle, —C₃₋₁₀cycloalkyl, —(CH₂)_(n)halo, said aryl and heterocycle optionallysubstituted with 1 to 3 groups of C₁₋₆alkyl, or halo,n represents 0-6; andm presents 0-1.

An embodiment of this invention is realized when m is 0.

Another embodiment of this invention is realized when m is 1.

Another embodiment of this invention is realized when R¹ is substitutedwith 1 to 3 groups of R^(a).

Another embodiment of this invention is realized when R¹ is selectedfrom the group consisting of thiazolyl, imidazolyl, imidazopyridyl,imidazopyrimidinyl, imidazopyridazinyl, pyrimidinyl, pyridyl, pyrazolyl,imidazothiazolyl, indolyl, isoxazolyl, oxazolyl, and pyrazopyrimidinyl,all of which are optionally substituted with 1 to 3 groups of R^(a). Asubembodiment of this invention is realized when R¹ is selected from thegroup consisting of substituted thiazolyl, imidazolyl, imidazopyridyl,imidazopyrimidinyl, imidazopyridazinyl, pyrimidinyl, pyridyl, pyrazolyl,imidazothiazolyl, indolyl, isoxazolyl, oxazolyl, and pyrazopyrimidinyl,substituted with 1 to 3 groups of R^(a). Another subembodiment of thisinvention is realized when R¹ is substituted pyrazolyl. Still anothersubembodiment of this invention is realized when R¹ is substitutedimidazopyridinyl. Still another subembodiment of this invention isrealized when R¹ is substituted pyrimidinyl. Yet another subembodimentof this invention is realized when R¹ is substituted pyridinyl. Afurther subembodiment of this invention is realized when R¹ issubstituted indolyl. Another subembodiment of this invention is realizedwhen R¹ is optionally substituted imidazothiazolyl. Still anothersubembodiment of this invention is realized when R¹ is substitutedthiazolyl. Another subembodiment of this invention is realized when R¹is substituted imidazopyridazinyl. Another subembodiment of thisinvention is realized when R¹ is substituted imidazolyl. Anothersubembodiment of this invention is realized when R¹ is substitutedpyrazopyrimidinyl. Another subembodiment of this invention is realizedwhen R¹ is substituted isoxazolyl. Still another subembodiment of thisinvention is realized when R¹ is substituted oxazolyl. Still anothersubembodiment of this invention is realized when R¹ is substitutedimidazopyrimidinyl.

Another embodiment of this invention is realized when R² representsoptionally substituted C₅₋₁₀ cycloalkyl.

Another embodiment of this invention is realized when R² represents—(CR₂)_(n)C₆₋₁₀ aryl and n is 0. A subembodiment of this invention isrealized when m is 1. Another subembodiment is realized when m is 0.Still another subembodiment of this invention is realized when R² isoptionally substituted phenyl or napthyl and in is 1. A furtherembodiment of this invention is realized when R² is substituted phenyland in is 1. Still another subembodiment of this invention is realizedwhen R² is optionally substituted phenyl or napthyl, preferably phenyl,and in is 0. A further embodiment of this invention is realized when R²is substituted phenyl and m is 0.

Another embodiment of this invention is realized when R² is a nitrogencontaining C₅₋₁₀ heterocycle optionally interrupted with 1 to 3additional heteroatoms selected from S, N, and O, said aryl andheterocycle optionally substituted with 1 to 3 groups of R^(a). Asubembodiment of this invention is realized when m is 0. Anotherembodiment of this invention is realized when R² is selected from thegroup consisting of thiazolyl, imidazolyl, imidazopyridyl,imidazopyrimidinyl, imidazopyridazinyl, pyrimidinyl, pyridyl, pyrazolyl,imidazothiazolyl, indolyl, isoxazolyl, oxazolyl, and pyrazopyrimidinyl,all of which are optionally substituted with 1 to 3 groups of R^(a). Asubembodiment of this invention is realized when R² is selected from thegroup consisting of substituted thiazolyl, imidazolyl, imidazopyridyl,imidazopyrimidinyl, imidazopyridazinyl, pyrimidinyl, pyridyl, pyrazolyl,imidazothiazolyl, indolyl, isoxazolyl, oxazolyl, and pyrazopyrimidinyl,substituted with 1 to 3 groups of R^(a) and m is 0. Anothersubembodiment of this invention is realized when R² is substitutedpyrazolyl and m is 0. Still another subembodiment of this invention isrealized when R² is substituted imidazopyridinyl and in is 0. Stillanother subembodiment of this invention is realized when R² issubstituted pyrimidinyl and m is 0. Yet another subembodiment of thisinvention is realized when R² is substituted pyridinyl and m is 0. Afurther subembodiment of this invention is realized when R² issubstituted indolyl and m is 0. Another subembodiment of this inventionis realized when R² is optionally substituted imidazothiazolyl and in is0. Still another subembodiment of this invention is realized when R² issubstituted thiazolyl and m is 0. Another subembodiment of thisinvention is realized when R² is substituted imidazopyridazinyl and m is0. Another subembodiment of this invention is realized when R² issubstituted imidazolyl and m is 0. Another subembodiment of thisinvention is realized when R² is substituted pyrazopyrimidinyl and in is0. Another subembodiment of this invention is realized when R² issubstituted isoxazolyl and in is 0. Still another subembodiment of thisinvention is realized when R² is substituted oxazolyl and in is 0. Stillanother subembodiment of this invention is realized when R² issubstituted imidazopyrimidinyl and in is 0.

Another embodiment of this invention is realized when both R¹ and R² arenitrogen containing C₅₋₁₀ heterocycle optionally interrupted with 1 to 3additional heteroatoms selected from S, N, and O, said aryl andheterocycle optionally substituted with 1 to 3 groups of R^(a) and m is0. A subembodiment of this invention is realized when m is 0 and one ofR¹ and R² is optionally substituted imidazopyridinyl and the other isselected from the group consisting thiazolyl, imidazopyridinyl,pyrimidinyl, pyrazolyl, pyridyl, and imidazopyridazinyl all of which areoptionally substituted with 1 to three groups of R^(a). A subembodimentof this invention is realized when one of R¹ and R² is optionallysubstituted imidazopyridinyl and the other is optionally substitutedimidazopyridinyl, or pyrazolyl. Another embodiment of this invention isrealized when both R¹ and R² are imidazopyridinyl. Another embodiment ofthis invention is realized when both R¹ and R² are pyrazolyl. Anotherembodiment of this invention is realized when both R¹ and R² arepyrimidinyl. Another embodiment of this invention is realized when bothR¹ and R² are pyridyl. Still another embodiment of this invention isrealized when both R¹ and R² are thiazolyl. Yet another embodiment ofthis invention is realized when one of R¹ and R² is pyrazolyl and theother is pyridyl. Yet another embodiment of this invention is realizedwhen one of R¹ and R² is pyrazolyl and the other is imidazopyridinyl.Yet another embodiment of this invention is realized when one of R¹ andR² is pyridyl and the other is imidazopyridinyl.

Another embodiment of this invention is realized when R¹ is selectedfrom the group consisting of optionally substituted imidazopyridinyl,imidazothiazolyl, pyrazolyl, and pyrimidinyl, R² is selected from thegroup consisting of optionally substituted phenyl and napthyl and in is0. Another embodiment of this invention is realized when R¹ is selectedfrom the group consisting of optionally substituted imidazopyridinyl,imidazothiazolyl, pyrazolyl, and pyrimidinyl, R² is selected from thegroup consisting of optionally substituted phenyl and napthyl and mis 1. A subembodiment of this invention is realized when R² isoptionally substituted phenyl and R¹ is selected from the groupconsisting of optionally substituted imidazopyridinyl, imidazothiazolyl,pyrazolyl, and pyrimidinyl. Another subembodiment of this invention isrealized when R² is optionally substituted naphthyl and R¹ is selectedfrom the group consisting of optionally substituted imidazopyridinyl,imidazothiazolyl, pyrazolyl, and pyrimidinyl.

Still in another embodiment of this invention R^(a) represents —CN,—C₁₋₄ haloalkyl, —OC₁₋₄ haloalkyl, SCF₃, —C₁₋₆alkyl, —(CHR)_(n)C₆₋₁₀aryl, —(CHR)_(n)C₅₋₁₀ heterocycle, —C₃₋₁₀ cycloalkyl, —O(CH₂)_(n)C₆₋₁₀aryl, —O—C₅₋₁₀ heterocycle, —O—, —(CH₂)_(n)halo, —OR, —NRR, —C(O)NRR, or—COR, said aryl and heterocycle optionally substituted with 1 to 3groups of R^(b). A subembodiment of this invention is realized whenR^(a) represents —CN, —CF₃, —OCF₃, SCF₃, —C₁₋₆alkyl, —(CH₂)_(n)halo,NRR, or —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl,oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, O(CH2)nphenyl, said pyrazolyl, furanyl, phenyl, pyridyl,tetrazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, O(CH₂)nphenyl optionally substituted with 1to 3 groups of R^(b).

Yet another embodiment of this invention is realized when R^(b)represents, —C₁₋₆alkyl, —(CH₂)_(n)C₁₋₄haloalkyl, OR, CN, halo, or —C₃₋₁₀cycloalkyl.

In another embodiment of the invention the compounds of formula I isrepresented by structural formula II:

or pharmaceutically acceptable salts there of wherein m, R^(a) and R²are as previously described. A subembodiment of the invention ofstructural formula II is realized when R^(a) is selected from the groupconsisting of —CN, —CF₃, —OCF₃, SCF₃, —C₁₋₆alkyl, —(CH₂)_(n)halo, NRR,or —C(O)NRR, pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl, oxazolyl,thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,O(CH₂)nphenyl, said pyrazolyl, furanyl, phenyl, pyridyl, tetrazolyl,oxazolyl, thiazolyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, O(CH₂)nphenyl optionally substituted with 1 to 3 groups ofR^(b).

In another embodiment of the invention the compounds of formula I isrepresented by structural formula III:

or pharmaceutically acceptable salts thereof wherein B is pyrazolyl orimidazolyl and m, R^(a) and R² are as previously described. Asubembodiment of the invention of formula III is realized when B ispyrazolyl. Still another subembodiment of the invention of formula IIIis realized when B is imidazolyl.

Still in another embodiment the compounds of formula I are representedby structural formula IV:

or pharmaceutically acceptable salts there of wherein A is pyridyl orpyrimidinyl and m and R^(a) are as previously described. A subembodimentof the invention of formula IV is realized when A is pyridyl. Anothersubembodiment of the invention of formula IV is realized when A ispyrimidinyl.

Examples of Compounds of this Invention Include Those in Table 1

TABLE 1 Exact Mass Compound Structure IUPAC Name [M + H]+  1

1,3-bis(2- phenylimidazo[1,2- a]pyridin-3-yl)urea 445.1  2

1-(1,3-diphenyl-1H- pyrazol-5-yl)-3- pyridin-2-ylurea 356.0  3

1,3-bis(3-methyl-1- phenyl-1H-pyrazol- 5-yl)urea 373.0  4

1-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)-3-naphthalen- 1-ylurea 343.1  5

1-(6-bromopyridin- 2-yl)-3-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)urea372.0  6

1-biphenyl-2-yl-3- (3-methyl-1-phenyl- 1H-pyrazol-5- yl)urea 369.0  7

1-(2,3- dimethylphenyl)-3- (3-methyl-1-phenyl- 1H-pyrazol-5- yl)urea321.0  8

1-(4-bromopyridin- 2-yl)-3-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)urea372.0  9

1-(1-phenyl-3- pyridin-4-yl-1H- pyrazol-5-yl)-3- pyridin-2-ylurea 357.010

1-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)-3-pyridin-2- ylurea 294.0 11

1-(5- methoxypyridin-2- yl)-3-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)urea324.0 12

1-(6-methyl-2- phenylpyridin-3-yl)- 3-pyridin-2-ylurea 305.0 13

1-biphenyl-2-yl-3- (2-methyl-4- phenylpyrimidin-5- yl)urea 381.2 14

1-(5-methyl-3- phenylisoxazol-4- yl)-3-[2- (trifluoromethyl) benzyl]urea376.0 15

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-naphthalen-1- ylurea 355.2 16

1-naphthalen-1-yl-3- (6- phenylimidazo[2,1- b][1,3]thiazol-5- yl)urea385.3 17

1,3-bis(2-methyl-4- phenylpyrimidin-5- yl)urea 397.1 18

1,3-bis[2- (methylsulfanyl)-4- phenylpyrimidin-5- yl]urea 461.3 19

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-(2-phenyl-1H- indol-3-yl)urea421.2 20

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-pyridin-2- ylurea 306.1 21

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-(2- phenylimidazo[1,2-a]pyridin-3-yl)urea 421.2 22

1-[2-chloro-4- (trifluoromethyl) phenyl]-3-(2- phenylimidazo[1,2-a]pyridin-3-yl)urea 431.1 23

1-(2- phenylimidazo[1,2- a]pyridin-3-yl)-3-[4- (trifluoromethyl)phenyl]urea 397.0 24

1-(2- phenylimidazo[1,2- a]pyridin-3-yl)-3-(2- phenylpyridin-3- yl)urea406.1 25

1-(3-methyl-1- phenyl-1H-pyrazol- 5-yl)-3-(2- phenylimidazo[1,2-a]pyridin-3-yl)urea 409.2 26

1-(2-methyl-4- phenyl-1,3-thiazol- 5-yl)-3-(2- phenylimidazo[1,2-a]pyridin-3-yl)urea 426.0 27

1-[3-(1-methyl-1H- imidazol-2- yl)phenyl]-3-(2- phenylimidazo[1,2-a]pyridin-3-yl)urea 409.3 28

ethyl 3-{[(2- phenylimidazo[1,2- a]pyridin-3- yl)carbamoyl]amino}imidazo[1,2- a]pyridine-2- carboxylate 441.2 29

1-(2- phenylimidazo[1,2- a]pyridin-3-yl)-3-[2- (1H-pyrazol-1-yl)imidazo[1,2- a]pyridin-3-yl]urea 435.2 30

1-(2- phenylimidazo[1,2- a]pyridin-3-yl)-3-(2- phenylimidazo[1,2-a]pyrimidin-3- yl)urea 446.2 31

1-(6-chloro-2- phenylimidazo[1,2- b]pyridazin-3-yl)-3- (2-phenylimidazo[1,2- a]pyridin-3-yl)urea 480.2 32

N-methyl-3-{[(2- phenylimidazo[1,2- a]pyridin-3- yl)carbamoyl]amino}imidazo[1,2- a]pyridine-2- carboxamide 426.1 33

1-(1-methyl-4- phenyl-1H-imidazol- 5-yl)-3-(2-methyl-4-phenyl-1,3-thiazol- 5-yl)urea 390.1 34

1-(1,2-dimethyl-4- phenyl-1H-imidazol- 5-yl)-3-(2-methyl-4-phenyl-1,3-thiazol- 5-yl)urea 404.3 35

1,3-bis(2-methyl-4- phenyl-1,3-thiazol- 5-yl)urea 407.3 36

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-(2-methyl-4- phenyl-1,3-thiazol-5-yl)urea 402.3 37

1-(2-methyl-4- phenyl-1,3-thiazol- 5-yl)-3-(2- phenylpyridin-3- yl)urea387.3 38

1-[5-fluoro-2- (trifluoromethyl) benzyl]-3-(1-phenyl- 1H-pyrazol-5-yl)urea 379.0 39

1-[4-fluoro-2- (trifluoromethyl) benzyl]-3-(1-phenyl- 1H-pyrazol-5-yl)urea 379.0 40

1-(2-methyl-4- phenylpyrimidin-5- yl)-3-{2- [(trifluoromethyl)sulfanyl]benzyl}urea 419.0 41

1-[(1S)-1- cyclohexylethyl]-3- (2-methyl-4- phenylpyrimidin-5- yl)urea339.1 42

1-(1-methyl-5- phenyl-1H-pyrazol- 4-yl)-3-[2- (trifluoromethyl)benzyl]urea 375.0 43

1-[5-fluoro-2- (trifluoromethyl) benzyl]-3-(2-methyl- 4-phenylpyrimidin-5- yl)urea 405.0 44

1-(1-phenyl-1H- pyrazol-5-yl)-3-{2- [(trifluoromethyl)sulfanyl]benzyl}urea 393.0 45

1-(5-methyl-3- phenylisoxazol-4- yl)-3-{2- [(trifluoromethyl)sulfanyl]benzyl}urea 408.0 46

1-(1-methyl-5- phenyl-1H-pyrazol- 4-yl)-3-[2- (trifluoromethoxy)benzyl]urea 391.0and pharmaceutically acceptable salts thereof.

The invention is also directed to methods of treating a patient(preferably a human) for diseases or disorders in which the TrkAreceptor may be involved, such as pain, inflammation, cancer,restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder,injury, or malfunction relating to dysmyelination or demyelination or adisease or disorder associated with abnormal activities of nerve growthfactor (NGF) receptor TrkA, by administering to the patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The invention is also directed to the use of a compound of the inventionfor treating a disease or disorder in which the TrkA receptor may beinvolved, such as pain, inflammation, cancer, restenosis,atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, ormalfunction relating to dysmyelination or demyelination or a disease ordisorder associated with abnormal activities of nerve growth factor(NGF) receptor TrkA, by administering to the patient a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The invention is also directed to medicaments or pharmaceuticalcompositions for the treatment of diseases or disorders in a patient(preferably a human) in which the TrkA receptor may be involved, such aspain, inflammation, cancer, restenosis, atherosclerosis, psoriasis,thrombosis, a disease, disorder, injury, or malfunction relating todysmyelination or demyelination or a disease or disorder associated withabnormal activities of nerve growth factor (NGF) receptor TrkA, whichcomprise a compound of the invention, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

The invention is also directed to a method for the manufacture of amedicament or a pharmaceutical composition for treating diseases inwhich TrkA receptor may be involved, such as pain, inflammation, cancer,restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder,injury, or malfunction relating to dysmyelination or demyelination or adisease or disorder associated with abnormal activities of nerve growthfactor (NGF) receptor TrkA comprising combining a compound of theinvention or a pharmaceutically acceptable salt thereof, with apharmaceutically acceptable carrier.

Where a variable occurs more than once in any formula of the invention,or in a substituent thereof, the individual occurrences of that variableare independent of each other, unless otherwise specified. Also,combinations of substituents/or variables are permissible only if suchcombinations result in stable compounds.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a saturated straight or branched chain hydrocarbonradical having the number of carbon atoms designated (e.g., C₁₋₁₀ alkylmeans an alkyl group having from one to ten carbon atoms). Preferredalkyl groups for use in the invention are C₁₋₆ alkyl groups, having fromone to six atoms. Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, andthe like. C₀ alkyl means a bond.

If and when R^(a) is —O— and attached to a carbon it is referred to as acarbonyl group and when it is attached to a nitrogen (e.g., nitrogenatom on a pyridyl group) or sulfur atom it is referred to a N-oxide andsulfoxide group, respectively.

As used herein, the term “alkenyl,” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon radicalhaving a single carbon-carbon double bond and the number of carbon atomsdesignated (e.g., C₂₋₁₀ alkenyl means an alkenyl group having from twoto ten carbon atoms). Preferred alkenyl groups for use in the inventionare C₂₋₆ alkenyl groups, having from two to six carbon atoms. Exemplaryalkenyl groups include ethenyl and propenyl.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent, means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated (e.g., C₃₋₁₂ cycloalkyl means acycloalkyl group having from three to twelve carbon atoms). The termcycloalkyl as used herein includes mono-, bi- and tricyclic saturatedcarbocycles, spirocycles, and bridged and fused ring carbocycles.

Preferred cycloalkyl groups for use in the invention are monocyclic C₃₋₈cycloalkyl groups, having from three to eight carbon atoms. Exemplarymonocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Exemplary bridged cycloalkylgroups include adamantyl and norbornyl. Exemplary fused cycloalkylgroups include decahydronaphthalene.

As used herein, the term “aryl,” by itself or as part of anothersubstituent, means an aromatic cyclic hydrocarbon radical. Preferredaryl groups have from six to ten carbons atoms. The term “aryl” includesmultiple ring systems as well as single ring systems. Preferred arylgroups for use in the invention include phenyl and naphthyl.

The term “aryl” also includes fused cyclic hydrocarbon rings which arepartially aromatic (i.e., one of the fused rings is aromatic and theother is non-aromatic). An exemplary aryl group which is partiallyaromatic is indanyl.

The term heterocyclyl, heterocycle or heterocyclic, as used herein,represents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from the group consisting of N, O, and S, andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. The term heterocyclyl, heterocycle orheterocyclic includes heteroaryl moieties. Examples of such heterocyclicelements include, but are not limited to, azepinyl, benzodioxolyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzotriazolyly, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, 1,3-dioxolanyl, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl,pyrazolopyridinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, thienyl, and triazolyl and N-oxides thereof.

When a heterocyclyl group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heteroaryl group,or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which hasa valence which permits substitution. Preferably, the substituent isbonded to a ring carbon atom. Similarly, when a heteroaryl group isdefined as a substituent herein, the point of attachment may be at aring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e.,a nitrogen, oxygen or sulfur), which has a valence which permitsattachment. Preferably, the attachment is at a ring carbon atom.

As used herein, the term “halo” or “halogen” includes fluoro, chloro,bromo and iodo.

As used herein, unless otherwise specifically defined, substitutedalkyl, substituted cycloalkyl, substituted aryl, substituted heteroaryl,and substituted heterocycle include moieties containing from 1 to 3substituents in addition to the point of attachment to the rest of thecompound. Preferably, such substituents are selected from the groupwhich includes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁-C₆alkyl)₂, NO₂, CN, (C₁-C₆ alkyl)O—, (aryl)O—, —OH, (C₁-C₆alkyl)S(O)_(m)—, (C₁-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, (C₁-C₆ alkyl)C(O)—,(C₁-C₆ alkyl)OC(O)—, (C₁-C₆ alkyl)OC(O)NH—, phenyl, pyridyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, isothiazolyl and C₁-C₂₀alkyl.

The compounds of the invention may have one or more asymmetric centers.Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both, and it isintended that all of the possible enantiomers and diastereomers inmixtures and as pure or partially purified compounds are included withinthe scope of this invention. The present invention is meant to encompassall such isomeric forms of the compounds of the invention. The presentinvention includes all stereoisomers of formulae I, II, III, or IV andpharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastereomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastereomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastereomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastereomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

In the compounds of the invention the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of generic formulaeformulae I, II, III, and IV. For example, different isotopic forms ofhydrogen (H) include protium (¹H) and deuterium (²H). Protium is thepredominant hydrogen isotope found in nature. Enriching for deuteriummay afford certain therapeutic advantages, such as increasing in vivohalf-life or reducing dosage requirements, or may provide a compounduseful as a standard for characterization of biological samples.Isotopically-enriched compounds within generic formulae formulae I, II,III, and IV can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

The term “substantially pure” means that the isolated material is atleast 90% pure, and preferably 95% pure, and even more preferably 99%pure as assayed by analytical techniques known in the art.

As used herein, the term “TrkA” refers to one of Trk's high affinitybinding protein kinase receptors that are activated by Neurotrophins(NT), a group of soluble growth factors Nerve Growth Factor (NGF),Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin 3-5 (NT 3-5).The Trk's are made up of three family members TrkA, TrkB and TrkC thatbind to and mediate the the signal transduction derived from theNeurotrophins. Inhibitors of the Trk/neutrophin pathway have beendemonstrated to be highly effective in numerous pre-clinical animalmodels of pain. The compounds of the invention are modulators of the Trkreceptors, particularly TrkA.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. The compoundsof the invention may be mono, di or tris salts, depending on the numberof acid functionalities present in the free base form of the compound.Free bases and salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like.

Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, diethylamine, trimethylamine, tripropylamine, tromethamine,and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroacetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric,para-toluenesulfonic acid, and the like.

The present invention is directed to the use of the compounds offormulae I, II, III, and IV disclosed herein as TrkA inhibitors in apatient or subject such as a mammal in need of such activity, comprisingthe administration of an effective amount of the compound. In additionto humans, a variety of other mammals can be treated according to themethod of the present invention.

The compounds of the present invention may have utility in treating orameliorating pain disorders (including pain associated with cancer,surgery, and bone fracture, acute pain, inflammatory pain andneuropathic pain). The compounds of formula formulae I, II, III, and IValso may beuseful for treating cancers including neuroblastoma, ovarian,pancreatic and colorectal cancer. Other conditions that may be treatedby the compounds of the invention include inflammation and certaininfectious diseases, interstitial cystitis, painful bladder syndrome,urinary incontinence, asthma, anorexia, atopic dermatitis, andpsoriasis. Treament of demyelination and dysmyelination, by promotingmyelination, neuronal survival, and oligodendrocyte differentiation viablocking Sp35-TrkA interaction may also be possible with the compoundsof the present invention.

The compounds of formula formulae I, II, III, IV may also be useful inthe treatment of bone-related diseases (e.g., those involved in boneresorption). Examples of bone-related diseases include metastatic bonedisease, treatment-induce bone loss, osteoporosis, rheumatoid arthritis,ankylosing spondylitis, Paget's disease, and periodontal disease.Another bone disorder or disease that can be treated with the compoundsof the claimed invention is metastatic tumor-induced osteolysis. Cancersknown to cause tumor induced osteolysis are hematological malignanciessuch as myeloma and lymphoma and solid tumors such as breast, prostate,lung, renal and thyroid.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological),chronic pain, dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), headache,migraine and cluster headache, headache, primary hyperalgesia, secondaryhyperalgesia, primary allodynia, secondary allodynia, or other paincaused by central sensitization.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally mammals such a human being, male or female, inwhom Trk-A, Trk-B and/or Trk-C modulation is desired. Thus, an aspect ofthe present invention is a method of treating diseases with an inhibitorof Trk-A, Trk-B and/or Trk-C comprising administering to said mammal oneor more compounds of formula formulae I, II, III, IV or apharmaceutically acceptable salt thereof in an amount effective to treator prevent said disorder. For purposes of this invention mammals includedogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys,chimpanzees or other apes or primates, for which treatment of the abovenoted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

Examples of combinations of the compounds include combinations withagents for the treatment of pain, for example steroids such asdexamethasone, cortisone, and fluticasone, non-steroidalanti-inflammatory agents, such as aspirin, diclofenac, duflunisal,fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2inhibitors, such as celecoxib, rofecoxib and valdecoxib; CB-2 agonists;VR-1 antagonists; bradykinin B 1 receptor antagonists; sodium channelblockers and antagonists; nitric oxide synthase (NOS) inhibitors(including iNOS and nNOS inhibitors); glycine site antagonists,including lacosamide; neuronal nicotinic agonists; NMDA antagonists;potassium channel openers; AMPA/kainate receptor antagonists; calciumchannel blockers, such as ziconotide; GABA-A receptor IO modulators(e.g., a GABA-A receptor agonist); matrix metalloprotease (MMP)inhibitors; thrombolytic agents; chemotherapeutic agents, opioidanalgesics such as codeine, fentanyl, hydromorphone, levorphanol,meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine,propoxyphene; neutrophil inhibitory factor (NIF); pramipexole,ropinirole; anticholinergics; amantadine; monoamine oxidase B15(“MAO-B”) inhibitors; 5HT receptor agonists or antagonists; mGlu5antagonists; alpha agonists; neuronal nicotinic agonists; NMDA receptoragonists or antagonists; NKI antagonists; selective serotonin reuptakeinhibitors (“SSRI”) and/or selective serotonin and norepinephrinereuptake inhibitors (“SSNRI”), such as duloxetine; tricyclicantidepressant drugs, norepinephrine modulators; lithium; valproate;gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan andsumatriptan.

Another aspect of the present invention is directed to a pharmaceuticalcomposition comprising a compound of formula formulae I, II, III, IV ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent or carrier. Still another aspect of the presentinvention is directed to a compound of formula formulae I, II, III, IV,or a pharmaceutically acceptable salt thereof, for use in the treatmentof a condition treatable with an inhibitor of Trk-A, Trk-B and/or Trk-C,such as the disorders, conditions and/or diseases described herein.Still another aspect is directed to an invention where use of a compoundof formula I or Ia or a pharmaceutically acceptable salt thereof in thetreatment of pain, cancer, inflammation, neurodegenerative disease ortypanosoma cruzi infection may be possible.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

In general, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active compound, which is a compound offormula formulae I, II, III, or IV is included in an amount sufficientto produce the desired effect upon the process or condition of diseases.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Other pharmaceutical compositions include aqueous suspensions, whichcontain the active materials in admixture with excipients suitable forthe manufacture of aqueous suspensions. In addition, oily suspensionsmay be formulated by suspending the active ingredient in a vegetableoil, for example arachis oil, olive oil, sesame oil or coconut oil, orin a mineral oil such as liquid paraffin. Oily suspensions may alsocontain various excipients. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions, which mayalso contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension, or in the form of sterilepowders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form mustbe sterile and must be effectively fluid for easy syringability. Thepharmaceutical compositions must be stable under the conditions ofmanufacture and storage; thus, preferably should be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared via conventional processing methods. As anexample, a cream or ointment is prepared by mixing hydrophilic materialand water, together with about 5 wt % to about 10 wt % of the compound,to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can also be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology).

The compositions containing compounds of the present invention mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. The term “unit dosageform” is taken to mean a single dose wherein all active and inactiveingredients are combined in a suitable system, such that the patient orperson administering the drug to the patient can open a single containeror package with the entire dose contained therein, and does not have tomix any components together from two or more containers or packages.Typical examples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples of unitdosage forms.

The compositions containing compounds of the present invention mayconveniently be presented as a kit, whereby two or more components,which may be active or inactive ingredients, carriers, diluents, and thelike, are provided with instructions for preparation of the actualdosage form by the patient or person administering the drug to thepatient. Such kits may be provided with all necessary materials andingredients contained therein, or they may contain instructions forusing or making materials or components that must be obtainedindependently by the patient or person administering the drug to thepatient.

When treating or ameliorating a disorder or disease for which compoundsof the present invention are indicated, generally satisfactory resultsare obtained when the compounds of the present invention areadministered at a daily dosage of from about 0.1 mg to about 100 mg perkg of animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thetotal daily dosage is from about 1.0 mg to about 2000 mg, preferablyfrom about 0.1 mg to about 20 mg per kg of body weight. In the case of a70 kg adult human, the total daily dose will generally be from about 7mg to about 1,400 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, preferably once or twice per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.005 mg to about 2.5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial. Unit dosage forms will generally contain between from about0.005 mg to about 1000 mg of the active ingredient, typically 0.005,0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twiceor three times a day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein.

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. Substituent numbering as shown in the schemesdoes not necessarily correlate to that used in the claims and often, forclarity, a single substituent is shown attached to the compound wheremultiple substituents are allowed under the definitions hereinabove.Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the schemes and examples herein, inaddition to other standard manipulations such as ester hydrolysis,cleavage of protecting groups, etc., as may be known in the literatureor exemplified in the experimental procedures.

During any of the synthetic sequences it may be necessary or desirableto protect sensitive or reactive groups on any of the moleculesconcerned. This may be achieved by means of conventional protectinggroups, such as those described in Protective Groups in OrganicChemistry, ed. J. F. W. McOmie, Plenum Press, 1973, and T. W. Greene &P/G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1999. The protecting groups may be removed at a convenient sequent stageusing methods known from the art.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

Reaction Scheme I illustrates the preparation of the compounds 1-3 ofthe invention. Amine 1-1 is treated with triphosgene, a base, and anappropriate amine to give urea 1-3.

Reaction Scheme II illustrates the preparation of the compounds 2-3 ofthe invention starting with amine 2-1. The material can be treated withCDI, a base, and an appropriate amine 2-2 to afford urea 2-3.Alternatively, urea 2-3 may be formed by exposure of amines 2-1 and 2-2to CDI under microwave heating.

Reaction Scheme III illustrates the preparation of the compounds 3-3 ofthe invention starting with isocyanate 3-1. The material can be treatedwith a base and an appropriate amine 3-2 to afford urea 3-3.

Reaction Scheme IV illustrates the preparation of the compounds 4-5 ofthe invention starting with amine 4-2. The amine 4-2 is attached to analdehyde-based resin (4-1) via exposure to sodium triacetoxyborohydridein the presence of acetic acid to afford amine 4-3. The resin boundamine 4-3 is then heated with the intermediate formed from the exposureof acid 4-4, DPPA and disopropylethylamine to afford urea 4-5. Releaseof the urea from the resin is effected by exposure to trifluoroaceticacid to yield urea 4-6.

Reaction Scheme V through VII illustrates the preparation of theintermediate amines of the type 1-1 which are used to prepare compoundsof the invention as described above.

Reaction Scheme V illustrates the preparation of the intermediate amines5-3 which are used to prepare compounds of the invention. Hydrazine 5-1is heated with cyanoamine 5-2 in the presence of an acid to afford amine5-3.

Reaction Scheme VI illustrates the preparation of the intermediateamines of the type 6-4 which are used to prepare compounds of theinvention. Ester 6-1 is alkylated with acetonitrile in the presence ofsodium hydride to afford cyano ketone 6-2. Conversion to amine 6-4 isthen effected by heating of the hydrazine 6-3 with cyano ketone 6-2.

Reaction Scheme VII illustrates the preparation of the intermediateamines of the type 7-3 which are used to prepare compounds of theinvention. Aryl chloride 7-1 is treated with an aryl boronic acid suchas 7-2 in the presence of a base/catalyst system such as Pd(dppf)Cl₂ andK₂CO₃ to afford amine 7-3.

Example of Reaction Scheme V Intermediate 1

3-Methyl-1-phenyl-1H-pyrazol-5-amine

A mixture of 3-aminobut-2-enenitrile (5.0 g, 61 mmol) andphenylhydrazine (7.3 g, 68 mmol) in 1N HCl (150 mL) was heated at refluxfor 16 h. The resulting mixture was cooled to ambient temperature, andthen basified to pH=9 with solid Na₂CO₃. The precipitate was collectedby filtration and dried in vacuum to give the desired title compound asa yellow solid. MS: m/z=174 (M+H).

Example of Reaction Scheme VI Intermediate 2

1-Phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine

A mixture of t-BuOK (6.8 g, 0.060 mol) and acetonitrile (2.5 g, 0.060mol) in anhydrous THF (100 mL) was stirred at 0° C. for 0.5 h. Methylisonicotinate (6.8 g, 0.050 mol) was added dropwise to the mixture at 0°C. and further stirred at 25° C. for 3 h. The reaction mixture was thenfiltered. Phenylhydrazine (5.4 g, 0.050 mmol) was then added to asolution of the filter cake in EtOH (30 mL). The resulting mixture wasthen stirred at 80° C. for 3 h then concentrated under reduce pressure.The residue was diluted with water (100 mL) and the resulting mixturewas extracted with EtOAc (50 mL×3). The combined organic layers werewashed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated.The residue was washed with MTBE (30 mL) to give the title compound as agrey solid. MS: m/z=237 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 8.54-8.56 (d,2H), 7.68 (br, 2H), 7.63 (br, 2H), 7.51 (br, 2H), 7.37 (br, 1H), 6.04(s, 1H), 5.56 (br, 2H).

Example of Reaction Scheme VI Intermediate 3

1,3-Diphenyl-1H-pyrazol-5-amine Step A: 3-Oxo-3-phenylpropanenitrile

A mixture of NaH (2.4 g, 0.060 mol, 60% dispersion in mineral oil) inanhydrous THF (100 mL) was stirred at 80° C. for 0.5 h, and then amixture of methyl benzoate (6.8 g, 0.050 mol) and CH₃CN (2.5 g, 0.060mol) in THF (20 mL) was added dropwise at 80° C. The reaction mixturewas stirred at 80° C. for 16 h. The reaction mixture was cooled and theexcess NaH was quenched with water (50 mL). The resulting mixture waswashed with EtOAc (100 mL) and acidified to pH=2 with HCl (2M). Theaqueous mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated to afford thetitle compound as a brown solid. MS: m/z=146 (M+H). ¹H NMR (300 MHz,CDCl₃) δ 7.84 (br, 2H), 7.60 (br, 1H), 7.46 (br, 2H), 4.02 (s, 2H).

Step B: 1,3-Diphenyl-1H-pyrazol-5-amine

To a solution of 3-oxo-3-phenylpropanenitrile (7.0 g, 0.048 mol) in EtOH(80 mL) was added dropwise phenylhydrazine (5.2 g, 0.048 mol). Themixture was stirred at 80° C. for 3 h. The mixture was cooled andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel with petroleum ether/EtOAc=5:1 to affordthe title compound as a yellow solid. MS: m/z=236 (M+H). ¹H NMR (300MHz, DMSO-d6) δ 7.75-7.77 (br, 2H), 7.65-7.68 (br, 2H), 7.48-7.54 (br,2H), 7.30-7.42 (br, 4H), 5.92 (s, 1H), 5.46 (br, 2H).

Example of Reaction Scheme VII Intermediate 4

6-Methyl-2-phenylpyridin-3-amine

A deoxygenated mixture of 2-chloro-6-methylpyridin-3-amine (200 mg, 1.56mmol), phenylboronic acid (381 mg, 3.13 mmol), Pd(dppf)₂Cl₂ (5 mg, 0.007mmol), and K₂CO₃ (646 mg, 4.68 mmol) in a 10:1 mixture of1,4-dioxane:water (33 mL) was heated at 80° C. for 18 h. The mixture wascooled and the organic layer was separated and washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The residue was further purifiedby TLC (PE:EtOAc=2:1) to give the title compound as a white solid. MS:m/z=171 (M+H).

1,3-Bis(2-phenylimidazo[1,2-a]pyridin-3-yl)urea

A solution of 2-phenylimidazo[1,2-a]pyridin-3-amine (1400 mg, 6.69 mmol)and triphosgene (1190 mg, 4.01 mmol) in DCM (20 mL) was stirred atambient temperature for 1.5 h. The suspension was filtered and thefilter cake was washed with DCM (6×3 mL), 5% MeOH/DCM (3×3 mL), and MeOH(1×3 mL), then dried to yield a white solid. The combined MeOH washeswere purified by prep-HPLC using a reversed phase C₁₈ column and elutingwith a gradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 50:50:0.1. The desiredfractions were concentrated and combined with the filtered solid. Thecombined solids were treated with 2M HCl in Et₂O (8 mL) and then driedunder vacuum to yield the title compound. MS: m/z=445.1 (M+H). ¹H NMR(400 MHz, D₂O) δ 8.36-8.21 (m, 2H), 7.80-7.36 (m, 16H).

1-(1,3-Diphenyl-1H-pyrazol-5-yl)-3-(pyridin-2-yl)urea

To a stirred solution of 1,3-diphenyl-1H-pyrazol-5-amine (200 mg, 0.85mmol) and pyridin-2-amine (140 mg, 1.50 mmol) in anhydrous THF (30 mL)was added triphosgene (5 mg, 0.28 mmol) and TEA (2 mL) at 25° C. Theresulting mixture was stirred at 50° C. for 6 h, cooled to ambienttemperature, and diluted with EtOAc and water. The organic layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by prep-HPLC using a reversedphase C₁₈ column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the title compound as awhite solid. MS: m/z=356 (M+H). ¹H NMR (400 MHz CD₃OD) δ 7.82 (m, 4H),7.68 (d, J=4.0 Hz, 4H), 7.60 (m, 1H), 7.42 (t, 2H), 7.35 (t, 1H), 7.01(s, 3H).

1,3-Bis(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a stirred solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (100 mg,0.85 mmol) in anhydrous THF (30 mL) was added TEA (3 mL) and triphosgene(5.0 mg, 0.28 mmol) at room temperature. After the addition wascomplete, the resulting mixture was heated at 50° C. for 16 h and thencooled and concentrated. The residue was suspended in DCM (5 mL),filtered and concentrated. The residue was purified by prep-HPLC using areversed phase C₁₈ column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the title compound as awhite solid. MS: m/z=373 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 7.53 (m, 6H),7.48 (d, J=6.8 Hz, 4H), 6.35 (s, 2H), 2.28 (s, 6H).

1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-3-(naphthalen-1-yl) urea

To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (100 mg, 0.58mmol) in THF (2 mL) was added triphosgene (57 mg, 0.19 mmol) and DIEA(150 mg, 1.2 mmol) at 0° C. The resulting mixture was stirred at 0° C.for 3 h and then treated with naphthalen-1-amine (83 mg, 0.58 mmol). Thereaction mixture was warmed to 25° C. and stirred for 12 h. Afterdilution with EtOAc (30 mL), the mixture was washed with water (10mL×2). The organic phase was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by prep-HPLC using a reversedphase C₁₈ column and eluting with a gradient ofH₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the title compound. MS:m/z=343 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=7.6 Hz, 2H), 7.65(d, J=8.4 Hz, 1H), 7.56 (d, J=7.0 Hz, 1H), 7.3-37.45 (m, 4H), 7.15˜7.26(m, 6H), 6.50 (s, 1H), 2.21 (s, 3H).

1-(6-Bromopyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared in the same manner as described forCompound 1 from 3-methyl-1-phenyl-1H-pyrazol-5-amine and6-bromopyridin-2-amine. MS: m/z=372/374 (M+H). ¹H NMR (400 MHz, CDCl₃) δ9.36 (br s, 1H), 7.56-7.46 (m, 5H), 7.41-7.37 (m, 1H), 7.07 (d, J=8.0Hz, 1H), 6.85 (m, 1H), 6.49 (s, 1H), 2.34 (s, 3H).

1-([1,1′-Biphenyl]-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared in the same manner as described forCompound 1 from 3-methyl-1-phenyl-1H-pyrazol-5-amine and[1,1′-biphenyl]-2-amine. MS: m/z=369 (M+H). ¹H NMR (400 MHz, CD₃OD) δ7.75 (d, J=6.8 Hz, 1H), 7.51-7.53 (m, 3H), 7.42-7.49 (m, 4H), 7.31-7.39(m, 4H), 7.21 (m, 2H), 6.32 (s, 1H), 2.29 (s, 3H).

1-(2,3-Dimethylphenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared in the same manner as described forCompound 1 from 3-methyl-1-phenyl-1H-pyrazol-5-amine and2,3-dimethylaniline. MS: m/z=321 (M+H). ¹H NMR (400 MHz, CD₃OD) δ7.55-7.48 (m, 5H), 7.25 (d, J=7.2 Hz, 1H), 6.95-7.05 (m, 2H), 6.39 (s,1H), 3.21 (m, 2H), 2.31 (d, J=11.6 Hz, 6H), 2.06 (s, 3H).

1-(4-Bromopyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

The title compound was prepared in the same manner as described forCompound 1 from 3-methyl-1-phenyl-1H-pyrazol-5-amine and4-bromopyridin-2-amine. MS: m/z=372/374 (M+H). ¹H NMR (400 MHz,DMSO-d6): δ11.16 (br, 1H), 10.04 (s, 1H) 7.74-7.76 (m, 1H), 7.4-7.59 (m,6H), 7.20-7.22 (m, 1H), 6.40 (s, 1H), 2.19 (s, 3H).

1-(1-Phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(pyridin-2-yl)urea

To a solution of 1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-amine (50 mg,0.21 mmol) in CH₃CN (2 mL) was added 2-aminopyridine (22 mg, 0.23 mmol)and CDI (45 mg, 0.28 mmol). The resulting mixture was sealed in amicrowave vial and heated at 120° C. for 20 min. The reaction mixturewas partitioned with water (10 mL) and DCM (10 mL). The organic layerwas separated and the water layer was extracted with DCM (10 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC using a reversed phase C₁₈ column and eluting with a gradientof H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the title compound asa white solid. MS: m/z=357 (M+H). ¹H NMR (400 MHz, DMSO-d6) δ 12.13 (b,1H), 10.11 (s, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 7.61-7.84 (m, 9H),6.97-7.17 (m, 3H).

1-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-3-(pyridin-2-yl)urea

To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (60.0 mg, 0.346mmol) in CH₃CN (15 mL) was added CDI (67.4 mg, 0.415 mmol). The mixturewas stirred at 50° C. for 1 h and pyridin-2-amine (32.6 mg, 0.346 mmol)was added. The reaction mixture was then further stirred at 50° C. for16 h. The reaction mixture was cooled, concentrated, and the residue waspurified by prep-HPLC using a reversed phase C₁₈ column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the titlecompound as a white powder. MS: m/z=294 (M+H). ¹H NMR (400 MHz, CD₃OD):δ 7.78 (d, J=4.8, 2H), 7.63-7.54 (m, 5H), 7.03 (d, J=3.2, 2H), 6.50 (s,1H), 2.30 (s, 3H).

1-(5-Methoxypyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea

To a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (50 mg, 0.29 mmol)in CH₃CN (2 mL) was added 4-methoxypyridin-2-amine (43 mg, 0.35 mmol)and CDI (56 mg, 0.35 mmol). The mixture was stirred for 16 h at 80° C.The reaction mixture was cooled, and concentrated, and the residue waspurified by prep-HPLC using a reversed phase C₁₈ column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the titlecompound as a white solid. MS: m/z=324 (M+H). ¹H NMR (400 MHz, CDCl₃) δ7.76-7.70 (m, 2H), 7.54-7.38 (m, 5H), 6.72 (m, 1H), 6.45 (s, 1H), 4.02(s, 3H), 2.35 (s, 3H).

1-(6-Methyl-2-phenylpyridin-3-yl)-3-(pyridin-2-yl)urea

The title compound was prepared in a similar manner as described forCompound 9 from 6-methyl-2-phenylpyridin-3-amine and pyridin-2-amine.MS: m/z=305 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.62 (s, 1H), 7.64 (m, 1H),7.56 (m, 5H), 7.49 (m, 1H), 7.28-7.30 (m, 1H), 6.85-6.89 (m, 1H),6.82-6.84 (m, 1H), 2.53 (s, 3H).

1-([1,1′-Biphenyl]-2-yl)-3-(2-methyl-4-phenylpyrimidin-5-yl)urea

A suspension of 2-methyl-4-phenylpyrimidin-5-amine hydrochloride (10.0mg, 0.045 mmol), 2-isocyanato-1,1′-biphenyl (10.6 mg, 0.054 mmol), andN,N,N-triethylamine (0.0130 mL, 0.090 mmol) in DCM (1 mL) was heated toreflux for 20 h, then concentrated. The residue was purified byprep-HPLC using a reversed phase C18 column and eluting with a gradientof H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to yield the title compound.MS: m/z=381.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 7.64 (d,J=7.7 Hz, 1H), 7.50-7.19 (m, 13H), 6.54 (s, 1H), 6.34 (s, 1H), 2.75 (s,3H).

1-(5-Methyl-3-phenylisoxazol-4-yl)-3-(2-(trifluoromethyl)benzyl)ureaStep A:

2-(Trifluoromethyl)benzylamine (14 mg, 0.8 mmol) was added toStratospheres PL-FDMP resin (0.16 mmol) in a solution 5% acetic acid inDCE (1 mL), followed by a solution of NaBH(OAc)₃ (85 mg, 0.4 mmol) in 5%acetic acid in DCE (1 mL). The reaction mixture was shaken for 36 h atambient temperature. The resin was filtered and washed 3 times withmethanol, DMF, isopropanol, and with DCM. The resin was then dried in avacuum oven for 2 h.

Step B:

A solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid (60 mg, 0.3mmol), DIEA (46 mg, 0.36 mmol), and DPPA (100 mg, 0.38 mmol) in toluene(1 mL) was shaken for 30 minutes at room temperature and then heated andshaken at 90° C. for 16 h. The reaction mixture was then added to theresin from step A and mixture shaken for 5 h at 90° C. The reactionmixture was filtered and the resin was washed with 3 times each withDMF, 1:1 acetic acid/DCM, water, isopropanol and finally with DCM. Theresin was then dried in a vacuum oven for 2 h.

Step C:

The resin from step B was added to a solution of 95% TFA/water (1.5 mL)and the resulting mixture was shaken for 2 h at ambient temperature. Theresin was filtered and washed with acetonitrile (3×1 mL). Water (1 mL)was added to the organic layer and the phases were mixed thoroughly andthe filtered solutions were dried overnight via Savant. The residue waspurified by prep-HPLC using a reversed phase C₁₈ column and eluting witha gradient of H₂O:CH₃CN:CF₃CO₂H—95:5:0.1 to 5:95:0.1, to give the desireproduct. MS: m/z 376.0 (M+H).

Biological Utility

TrkA functional activity was measured using a DiscoverX PathHunterassay. In this assay, U2OS cells are express TrkA receptor as a fusionwith the weakly complementing fragment of B-galactosidase, whichDiscoverX calls “Prolink (PK)”; additionally, Shcl is fused with alarger fragment, which is called “Enzyme Acceptor (EA)”. Activation ofthe TrkA receptor, upon NGF addition, results in the kinase domain beingphosphorylated, resulting in subsequent recruitment of Shcl-EA protein.That recruitment results in an active B-galactosidase enzyme that isdetected by addition of a chemiluminescent substrate.

All reagents were purchased from DiscoverX, except for the receptoragonists (NGF, BDNF, NT3) which were purchased from Peprotech. Cellswere expanded and frozen into cryovials (TrkA p75 @ passage 13, 1.5×10̂7cells/vial; TrkC p75 @ passage 11, 1.5×10̂7 cells/vial in InVitrogenRecovery Cell Freezing media), and stored in the vapor phase of liquidnitrogen, and thawed immediately before use. Thawed cells were added toa 384-well plate (BD Falcon 384-well white/clear, TC surface 120 uLassay plates (353963), 20 uL of 0.375e6 cells/mL=>7500 cells/well), andallowed to incubate overnight. Compound (10 mM starting dose: 202.5 nLcompound yielding 0.81% DMSO final in total assay volume and startingdoses 81 uM) was added the following morning and allowed to incubate oncells for 1 hour. Then, 5 uL EC80 of agonist (NGF for TrkA; BDNF forTrkB; NT3 for TrkC) was added and allowed to incubate for 3 hours atroom temperature. DiscoverX PathHunter detection reagent is added (12 uLto plate and components diluted in parts as per kit instructions) andthe plate is further incubated for 1 hour in the dark. The plate is readvia luminescence on the Perkin Elmer Envision.

The percent inhibition was calculated for each compound concentration,and the IC₅₀ was determined using Equation 1 below.

$\begin{matrix}{{\% \mspace{14mu} {Inhibition}} = \left( {{Max} + \frac{\left( {{Max} - {Min}} \right)}{1 + \left( \frac{Conc}{{IC}_{50}} \right)^{Hill}}} \right)} & {{Equation}\mspace{14mu} 1}\end{matrix}$

TABLE 2 Compound TrkA IC₅₀ (nM) 1 82 2 160 3 2700 4 590 5 4800 6 420 74800 8 3000 9 350 10 1800 11 3400 12 1100 13 2300 14 350 15 4100 16 29017 1400 18 280 19 570 20 4000 21 150 22 4200 23 4300 24 450 25 520 26 4827 1600 28 460 29 1400 30 1500 31 1000 32 1000 33 4000 34 4100 35 610 362300 37 1800 38 1100 39 1400 40 680 41 2100 42 1400 43 1400 44 420 45420 46 1600

The following abbreviations are used throughout the text:

-   -   Me: methyl    -   Et: ethyl    -   Bu: butyl    -   t-Bu: tert-butyl    -   Ar: aryl    -   Ph: phenyl    -   Bn: benzyl    -   Ac: acetyl    -   DMFDMA N,N-dimethylformamide dimethyl acetal    -   DMSO dimethylsulfoxide    -   DMF N,N-dimethylformamide    -   DMEM: Dulbecco's Modified Eagle Medium (High Glucose)    -   THF: tetrahydrofuran    -   TEA: triethylamine    -   rt: room temperature    -   aq: aqueous    -   HPLC: high performance liquid chromatography    -   MS: mass spectrometry    -   RB: round bottom    -   CDI 1,1′-Carbonyldiimidazole    -   DCE 1,2-Dichlorethane    -   HCl Hydrochloric acid    -   ° C. degrees Celcius    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene    -   DMSO methyl sulfoxide    -   ATP adenosine triphosphate

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore, that the invention be defined by the scope ofthe claims that follow and that such claims be interpreted as broadly asis reasonable.

What is claimed is:
 1. A compound of formula I or Ia:

and pharmaceutically acceptable salts thereof, wherein: R representshydrogen, or C₁₋₆ alkyl; R¹ represents a nitrogen containing C₅₋₁₀heterocycle optionally interrupted with 1 to 3 additional heteroatomsselected from S, N, and O, said heterocycle optionally substituted with1 to 3 groups of R^(a); R² represents —(CR₂)_(n)C₃₋₁₀ cycloalkyl,—(CR₂)_(n)C₆₋₁₀ aryl or a nitrogen containing C₅₋₁₀ heterocycleoptionally interrupted with 1 to 3 additional heteroatoms selected fromS, N, and O, said cycloalkyl, aryl and heterocycle optionallysubstituted with 1 to 3 groups of R^(a); R^(a) represents —CN, —O—,—(CH₂)_(n)C₁₋₄haloalkyl, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₁₋₆alkynyl,—(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀ heterocycle, —C₃₋₁₀ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₀ aryl, —O—C₅₋₁₀ heterocycle, —C(O)CF₃, —(CH₂)_(n)halo,—OR, —NRR, NHC₆₋₁₀aryl, —SCF₃, SO₂CF₃, OC(F)₂Cl, OC₁₋₄ haloalkyl,C(O)NRR, SO₂R, SO₂NRR, OC(F)₂C(F)₃, S(O)₂CH(F)₂, OC(F)₂CH(F)₂,C(CH₃)₂C≡N, —COC₆₋₁₀ aryl, or —CO₂R, said cycloalkyl, alkyl, aryl andheterocycle optionally substituted with 1 to 3 groups of R^(b); R^(b)represents, —CN, —(CH₂)_(n)C₁₋₄haloalkyl, —OR, —C₁₋₆alkyl, (CH₂)_(n)OR,—(CHR)_(n)C₆₋₁₀ aryl, —(CHR)_(n)C₅₋₁₀ heterocycle, —C₃₋₁₀ cycloalkyl,—(CH₂)_(n)halo, said aryl and heterocycle optionally substituted with 1to 3 groups of C₁₋₆alkyl, or halo, n represents 0-6; and m presents 0-1.2. The compound according to claim 1 wherein R¹ is selected from thegroup consisting of thiazolyl, imidazolyl, imidazopyridyl,imidazopyrimidinyl, imidazopyridazinyl, pyrimidinyl, pyridyl, pyrazolyl,imidazothiazolyl, indolyl, isoxazolyl, oxazolyl, and pyrazopyrimidinyl,all of which are optionally substituted with 1 to 3 groups of R^(a). 3.The compound according to claim 1 wherein R² represents —(CR₂)_(n)C₆₋₁₀aryl.
 4. The compound according to claim 3 wherein m is
 1. 5. Thecompound according to claim 3 wherein m is
 0. 6. The compound accordingto claim 1 wherein R² is a nitrogen containing C₅₋₁₀ heterocycleoptionally interrupted with 1 to 3 additional heteroatoms selected fromS, N, and O, said aryl and heterocycle optionally substituted with 1 to3 groups of R^(a) and in is
 0. 7. The compound according to claim 6wherein R² is selected from the group consisting of thiazolyl,imidazolyl, imidazopyridyl, imidazopyrimidinyl, imidazopyridazinyl,pyrimidinyl, pyridyl, pyrazolyl, imidazothiazolyl, indolyl, isoxazolyl,oxazolyl, and pyrazopyrimidinyl, all of which are optionally substitutedwith 1 to 3 groups of R^(a).
 8. The compound according to claim 1wherein both R¹ and R² are nitrogen containing C₅₋₁₀ heterocycleoptionally interrupted with 1 to 3 additional heteroatoms selected fromS, N, and O, said aryl and heterocycle optionally substituted with 1 to3 groups of R^(a) and m is
 0. 9. The compound according to claim 8wherein one of R¹ and R² is optionally substituted imidazopyridinyl andthe other is selected from the group consisting thiazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, pyridyl, andimidazopyridazinyl all of which are optionally substituted with 1 tothree groups of R^(a).
 10. The compound according to claim 8 wherein oneof R¹ and R² is optionally substituted imidazopyridinyl and the other isoptionally substituted imidazopyridinyl, pyridyl or pyrazolyl.
 11. Thecompound according to claim 8 wherein R¹ and R² both areimidazopyridinyl, pyrazolyl, pyrimidinyl, pyridyl, or thiazolyl.
 12. Thecompound according to claim 1 wherein R¹ is selected from the groupconsisting of optionally substituted imidazopyridinyl, imidazothiazolyl,pyrazolyl, and pyrimidinyl, and R² is —(CR₂)_(n)C₆₋₁₀ aryl, said arylselected from the group consisting of optionally substituted phenyl andnapthyl.
 13. The compound according to claim 1 represented by structuralformula II:

or pharmaceutically acceptable salts there of.
 14. The compoundaccording to claim 1 represented by structural formula III:

or pharmaceutically acceptable salts there of wherein B is pyrazolyl orimidazolyl.
 15. The compound according to claim 1 represented bystructural formula IV:

or pharmaceutically acceptable salts there of wherein A is pyridyl orpyrimidinyl.
 16. A compound which is:1,3-bis(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-pyridin-2-ylurea;1,3-bis(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-naphthalen-1-ylurea;1-(6-bromopyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-biphenyl-2-yl-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-(2,3-dimethylphenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-(4-bromopyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-(1-phenyl-3-pyridin-4-yl-1H-pyrazol-5-yl)-3-pyridin-2-ylurea;1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-pyridin-2-ylurea;1-(5-methoxypyridin-2-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;1-(6-methyl-2-phenylpyridin-3-yl)-3-pyridin-2-ylurea;1-biphenyl-2-yl-3-(2-methyl-4-phenylpyrimidin-5-yl)urea;1-(5-methyl-3-phenylisoxazol-4-yl)-3-[2-(trifluoromethyl)benzyl]urea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-naphthalen-1-ylurea;1-naphthalen-1-yl-3-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)urea;1,3-bis(2-methyl-4-phenylpyrimidin-5-yl)urea;1,3-bis[2-(methylsulfanyl)-4-phenylpyrimidin-5-yl]urea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-(2-phenyl-1H-indol-3-yl)urea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-pyridin-2-ylurea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;1-[2-chloro-4-(trifluoromethyl)phenyl]-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-[4-(trifluoromethyl)phenyl]urea;1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-(2-phenylpyridin-3-yl)urea;1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-3(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;1-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;1-[3-(1-methyl-1H-imidazol-2-yl)phenyl]-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;ethyl3-{[(2-phenylimidazo[1,2-a]pyridin-3-yl)carbamoyl]amino}imidazo[1,2-a]pyridine-2-carboxylate;1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-[2-(1H-pyrazol-1-yl)imidazo[1,2-a]pyridin-3-yl]urea;1-(2-phenylimidazo[1,2-a]pyridin-3-yl)-3-(2-phenylimidazo[1,2-a]pyrimidin-3-yl)urea;1-(6-chloro-2-phenylimidazo[1,2-b]pyridazin-3-yl)-3-(2-phenylimidazo[1,2-a]pyridin-3-yl)urea;N-methyl-3-{[(2-phenylimidazo[1,2-a]pyridin-3-yl)carbamoyl]amino}imidazo[1,2-a]pyridine-2-carboxamide;1-(1-methyl-4-phenyl-1H-imidazol-5-yl)-3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)urea;1-(1,2-dimethyl-4-phenyl-1H-imidazol-5-yl)-3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)urea;1,3-bis(2-methyl-4-phenyl-1,3-thiazol-5-yl)urea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)urea;1-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-3-(2-phenylpyridin-3-yl)urea;1-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-3-(2-phenylpyridin-3-yl)urea;1-[4-fluoro-2-(trifluoromethyl)benzyl]-3-(1-phenyl-1H-pyrazol-5-yl)urea;1-(2-methyl-4-phenylpyrimidin-5-yl)-3-{2-[(trifluoromethyl)sulfanyl]benzyl}urea;1-[(1S)-1-cyclohexylethyl]-3-(2-methyl-4-phenylpyrimidin-5-yl)urea;1-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-3-[2-(trifluoromethyl)benzyl]urea;1-[5-fluoro-2-(trifluoromethyl)benzyl]-3-(2-methyl-4-phenylpyrimidin-5-yl)urea;1-(1-phenyl-1H-pyrazol-5-yl)-3-{2-[(trifluoromethyl)sulfanyl]benzyl}urea;1-(5-methyl-3-phenylisoxazol-4-yl)-3-{2-[(trifluoromethyl)sulfanyl]benzyl}urea;1-(1-methyl-5-phenyl-1H-pyrazol-4-yl)-3-[2-(trifluoromethoxy)benzyl]ureaand pharmaceutically acceptable salts thereof.
 17. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 18. Use of a compound of claim 1 ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, for the manufacture of a medicament for thetreatment of a disease or disorder mediated by the Trk receptors,wherein said disease or disorder is selected from the group consistingof pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis,thrombosis, a disease, disorder, injury, or malfunction relating todysmyelination or demyelination or a disease or disorder associated withabnormal activities of nerve growth factor (NGF) receptor Trk-A, Trk-Band/or Trk-C.
 19. A compound according to claim 1 for use as amedicament.
 20. A method of treating a disease or disorder mediated bythe Trk receptors, wherein said disease or disorder is selected from thegroup consisting of pain, inflammation, cancer, restenosis,atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, ormalfunction relating to dysmyelination or demyelination or a disease ordisorder associated with abnormal activities of nerve growth factor(NGF) receptor Trk-A, Trk-B and/or Trk-C in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.